1
Autoregulatory capacity and compensatory reserve in an experimental model of acute shunt failure Kiran J. Agarwal-Harding 1 , Marek Czosnyka, Ph.D. 2 1 Harvard Medical School, Oliver Wendell Holmes Society, Class of 2013, 2 Neurosurgery Unit, Department of Clinical Neurosciences, Addenbrooke Hospital, University of Cambridge Abstract Hydrocephalus arises due to cerebrospinal fluid (CSF) volume expansion in the skull causing intracranial hypertension (ICH). It is seen clinically in children and in adults, and is often treated by surgical placement of a ventriculoperitoneal shunt. Shunt malfunction, particularly acute shunt failure is a medical emergency that is life threatening. Although in most cases shunt malfunction is easily diagnosed, in some cases, patients can present with confusing symptoms for which intracranial pressure (ICP) monitoring can provide valuable information for surgical decision-making. However, ICP monitoring by invasive monitor poses the risk of infection and hemorrhage. The use of noninvasive monitoring tools to assess intracranial pressure and cerebral hemodynamics could assist in management of patients with acute shunt failure, as well as shed light on the physiology of ICH by CSF volume expansion. Understanding the physiology of ICH can also help us understand other diseases where CSF circulation and cerebral hemodynamics are altered, such as traumatic brain injury and stroke. In this study, we assessed the behavior of various physiological calculated parameters during deep ICH caused by CSF volume expansion, and we assessed the validity of these parameters to approximate healthy ranges of cerebral perfusion pressure (CPP). As a model of acute shunt failure, 51 rabbits with basilar-dependent cerebral perfusion (bilateral carotid ligation) had a steady infusion of mock CSF (saline 0.9%) into the subarachnoid space until an ICP rise and Cushing response were observed. ICP and arterial blood pressure (ABP) were monitored continuously. Transcranial Doppler insonation of the middle cerebral artery was used to monitor arterial blood inflow velocity, and Laser Doppler Flowmetry (LDF) was used to monitor microvascular changes in perfusion of the cortex. Correlation coefficients were calculated real-time between CPP and LDF (LDx), ICP and ABP (PRx), ABP and the amplitude of the ICP waveform (PAX), and ICP and the amplitude of the ICP waveform (RAP). Binned analysis was conducted to determine mean values of parameters at ranges of ICP and CPP. All parameters increased significantly with increasing ICP indicating a loss of autoregulation in small vessels and compensatory reserve during ICH. RAP in particular showed a trend of increasing to a maximum as compensatory reserve was depleted as ICP increased and CPP decreased. LDx, PRx, PAX all showed a parabolic relationship with CPP, indicating an optimal range of CPP where these parameters were minimized (between 50 and 90mmHg). These results indicate that during CSF volume expansion ICH, cerebral autoregulation occurs in the small vessels to maintain CPP. This study also shows that LDx, PRx, PAX, and RAP are useful parameters in determining optimal ranges of CPP in patients with acute shunt failure, and may prove helpful in managing patients with hydrocephalus and other ICH-related illnesses. Introduction Hydrocephalus and acute shunt failure • Affects pediatric and adult patients • It is the most common reason for neurosurgery in children in the United States • Incidence is even higher in developing countries • Preferred treatment is placement of an ventriculoperitoneal shunt • 50% of VP shunts fail within 2 years • Failure of the VP shunt can lead to life-threatening acute intracranial hypertension (ICH) Cerebral autoregulation • Occurs to maintain steady cerebral blood flow (CBF) and cerebral perfusion • Perfusion is inversely related to intracranial pressure (ICP) o CPP = ABP-ICP • Autoregulation can be overwhelmed, leading to tissue damage and poor prognosis • High ICP plateau-waves are clinically related to poor patient outcomes • Investigation has been done into noninvasive means of measuring auto- regulation to monitor patients with ICH Calculated physiological parameters: LDx, PRx, PAX, RAP • Parameters that have been shown to indicate the autoregulatory capacity of small vessels and the compensatory reserve in the cerebral vasculature • Calculated using data that can be obtained noninvasively • Have been shown individually to correlate in a clinical setting with ICP changes • Further work is necessary to determine the changes seen in these parameters with controlled increased intracranial pressure that is extravascular in origin Objectives • Understand the physiology of ICP in an experimental model • Determine the ability of various physiological calculated parameters to report increases in ICP and indicate brain health • Determine the validity of various physiological calculated parameters to approximate healthy ranges of CPP Hypothesis • Deep intracranial hypertension will cause an increase in LDx, PRx, PAX, and RAP as autoregulation is compromised by high ICP and the compensatory reserve of small blood vessels is depleted. • The parameters LDx, PRx, PAX and RAP will indicate ranges of healthy CPP in the rabbit where autoregulation is occurring appropriately. Significance • Application to patients with acute shunt failure and acute hydrocephalus • Understanding the physiology of disease can help determine the risks these patients face and potential treatments • Validation of these parameters as tools in assessing autoregulation in small vessels • Application to patients with any form of intracranial hypertension including stroke, traumatic brain injury, and cerebral malaria • Current ICP monitoring is invasive, discontinuous, and requires skilled professionals • Noninvasive monitoring would be cheaper, safer, and more widely applicable in the clinical setting Methods Experimental Model • New Zealand White Rabbits • Basilar artery dependent cerebral perfusion (bilateral common carotid ligation) • Mock CSF (saline 0.9%) infused into subarachnoid space at site of lumbar puncture • Infusion was continued at a controlled rate to elevate ICP until a Cushing response was seen Monitoring of… • ICP: intraparenchymally inserted transducer • ABP: transducer in radial artery • Arterial blood inflow velocity: TCD insonation of MCA (FVX) • Laser Doppler Flowmetry (LDF) • PaCO2: from ventilator Data processing • Artifacts removed manually • Regions of baseline ICP and regions where the Cushing response was evident were identified manually and removed • Parameters (LDx, PRx, PAX, RAP) were calculated using raw data • All parameters had a calculation period of 5 minutes with an update period of 10 seconds Calculations • LDx o Correlation coefficient between CPP and LDF o Indicates autoregulatory capacity in small vessels as measured at the cortex using laser Doppler flowmetry • PRx o Correlation coefficient between ICP and ABP o Pressure reactivity, autoregulatory ability in small vessels • PAX o Correlation coefficient between ABP and the amplitude of the ICP waveform o Indicates compensatory reserve • RAP o Correlation coefficient between ICP and the amplitude of the ICP waveform o Indicates compensatory reserve Binned analysis • 55 rabbits • Values analyzed for full range of ICP and CPP • Figures show values averaged across ranges of ICP and CPP • Bins are values given in x-axis ±5 • Means were excluded if they represented less than 2% of the data • For all parameters showing a linear regression, the correlation coefficient was calculated, the coefficient was transformed using the Fisher transform, and the significance was tested (α<0.05) • Nonlinear regressions are shown with R2 values, square root taken to find R, the coefficient was transformed using the Fisher transform, and the significance was tested (α<0.05) Comparative analysis • Paired analysis of 51 rabbits • All parameters when ICP <25mmHg compared to when ICP≥25mmHg • Figures show mean values for the specified variable, error bars show ±one standard deviation • Paired t-tests were performed on the means to test for a significant difference for each variable before and during Cushing response (α<0.05) Results Binned Analysis Summary • ABP increases with increasing ICP, as expected • ABP decreases with decreasing CPP indicating poorly controlled blood pressure in the experimental model, possibly due to the trauma of the experimental procedure • HR decreases with increasing ICP, as expected, and HR v. CPP mirrors this same trend • Amplitude of the ICP waveform decreases with increasing ICP, as expected, and Amp_ICP v. CPP mirrors this same trend • FV v. CPP demonstrated Lassen curve showing optimal CPP range • LDx, PRx, PAX, and RAP all increase significantly with increasing ICP indicating a loss of autoregulation in small vessels and compensatory reserve as ICP increases • RAP in particular shows a trend of increasing to a maximum as compensatory reserve is depleted • LDx, PRx, PAX all show a parabolic relationship with CPP, indicating an optimal range of CPP where these parameters are minimized (between 50 and 90mmHg) • RAP shows a loss of compensatory reserve as ICP increases and as CPP decreases Comparative Analysis Summary • HR , ABP, and amplitude of ICP were significantly different from low to high ICP, indicating an expected physiological response • All parameters showed a significant different from low to high ICP Discussion • During CSF volume expansion ICH, cerebral autoregulation occurs in the small vessels to maintain CPP • LDx, PRx, PAX, and RAP are useful parameters in determining optimal ranges of CPP in patients with acute shunt failure • These parameters change with changing ICP and can be monitored continuously and noninvasively • These parameters may prove helpful in managing patients with hydrocephalus and other ICH-related illnesses Acknowledgements Special thanks to Dr. Peter Smielewski , Dr. Magdalena Kasprowicz, and Dr. Enrico Sorrentino at the University of Cambridge for help with data collection and analysis. Thank you also to the National Institutes of Health Graduate Partnership Program and Harvard Medical School Office of Enrichment Programs. References Kim DJ, Kasprowicz M, Carrera E, et al. The monitoring of relative changes in compartmental compliances of brain. Physiol Meas. Jul 2009;30(7):647-659. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths.: Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control;2006. Bazarian JJ, McClung J, Shah MN, Ting Cheng Y, Flesher W, Kraus J. Mild traumatic brain injury in the United States, 1998–2000. Brain Injury. 2005;19(2):85-91. Langlois JA, Rutland-Brown W, Thomas KE. The incidence of traumatic brain injury among children in the United States: differences by race. J Head Trauma Rehabil. May-Jun 2005;20(3):229-238. Maramattom BV, Wijdicks EFM. Uncal herniation. Archives of Neurology. Dec 2005;62(12):1932-1935. Bazarian JJ, Zhong J, Blyth B, Zhu T, Kavcic V, Peterson D. Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: a pilot study. J Neurotrauma. Sep 2007;24(9):1447-1459. Ropper A, Brown R. Adam's and Victor's Principles of Neurology, Eighth Edition. New York: McGraw-Hill Companies, Inc; 2005. Kandel E, Schwartz J, Jessell T. Principles of Neural Science. New York: McGraw Hill; 2000. Hayashi M, Handa Y, Kobayashi H, Kawano H, Ishii H, Hirose S. Plateau-wave phenomenon (I). Correlation between the appearance of plateau waves and CSF circulation in patients with intracranial hypertension. Brain. Dec 1991;114 ( Pt 6):2681-2691. Hayashi M, Kobayashi H, Handa Y, Kawano H, Hirose S, Ishii H. Plateau-wave phenomenon (II). Occurrence of brain herniation in patients with and without plateau waves. Brain. Dec 1991;114 ( Pt 6):2693-2699. Schmidt B, Czosnyka M, Raabe A, et al. Adaptive noninvasive assessment of intracranial pressure and cerebral autoregulation. Stroke. Jan 2003;34(1):84-89. Aaslid R. Cerebral autoregulation and vasomotor reactivity. Front Neurol Neurosci. 2006;21:216-228. Panerai RB, Kerins V, Fan L, Yeoman PM, Hope T, Evans DH. Association between dynamic cerebral autoregulation and mortality in severe head injury. Br J Neurosurg. Oct 2004;18(5):471-479. Alperin N, Sivaramakrishnan A, Lichtor T. Magnetic resonance imaging-based measurements of cerebrospinal fluid and blood flow as indicators of intracranial compliance in patients with Chiari malformation. J Neurosurg. Jul 2005;103(1):46-52. Narayanan N, Leffler CW, Czosnyka M, Daley ML. Assessment of cerebrovascular resistance with model of cerebrovascular pressure transmission. Acta Neurochir Suppl. 2008;102:37-41. Baledent O, Fin L, Khuoy L, et al. Brain hydrodynamics study by phase-contrast magnetic resonance imaging and transcranial color doppler. J Magn Reson Imaging. Nov 2006;24(5):995-1004. Czosnyka M, Richards HK, Czosnyka Z, Piechnik S, Pickard JD, Chir M. Vascular components of cerebrospinal fluid compensation. J Neurosurg. Apr 1999;90(4):752- 759. Brain herniation Intracranial hypertension Acute shunt failure Poor cerebral perfusion Tissue Necrosis Long term effects Cerebrovascular autoregulation Sample of raw recording data
